Our overall goal is to learn more about pulmonary O2 toxicity by investigating endogenous and exogenous means of protecting the lung from oxidant-induced dysfunction. Our three primary areas of investigation include: (1) Protection from pulmonary O2 toxicity by treatment with the exogenous agent, endotoxin, and the mechanism(s) of endotoxin's protective action in the hyperoxic setting; (2) Role of the endogenous defense systems of the lung (the antioxidant enzymes) in protection from hyperoxic toxicity, and the importance of these enzymes in mediating the protective effect conferred by endotoxin treatment; and, (3) A further investigation of the mechanism(s) that might explain the relative tolerance of newborn or immature animals to prolonged exposures to high concentrations of O2 compared to adult animals. Other related studies will be concerned with: (1) Endotoxin's potential protective effect against oxidant-induced injury associated with paraquat, and the chemotherapeutic agents bleomycin, adriamycin, and nitrofurantoin; (2) The role of indoleamine 2,3-dioxygenase as a pulmonary antioxidant enzyme; (3) The possibility of augmenting the intracellular antioxidant capabilities of the lung by use of exogenous superoxide dismutase (SOD) in a liposomal-encapsulated preparation; and, (4) The effect of various clinically-relevant conditions on the O2 tolerance of immature animals, including prenatal corticosteroid treatment, nutritional deficiency and gestational diabetes. We plan to use standard means to evaluate lung toxicity, and standard assays for assessing lung biochemical responses to toxic exposures to oxidant agents. In addition, morphometric methods will be used for assessing cellular and subcellular differences in the lungs of O2-resistant and O2-susceptible groups of adult and newborn animals. These proposed studies should help us to better understand how the lung is biochemically and morphologically adapted for protection against important sources of hyper-oxidant stress, and how through exogenous means the inherent protective mechanisms of the lung may be either significantly enhanced or significantly impaired.